: Damage to the neuronal cytoskeleton is an important pathological feature of a number of central nervous system injuries and neurodegenerative diseases. However, we have little information on cytoskeletal damage produced by traumatic brain injury (TBI) or mechanisms mediating this cytoskeletal damage. Thus, we will employ a rodent model of TBI to characterize regional and cellular changes in cytoskeletal proteins and to examine possible proteolytic mechanisms of cytoskeletal loss. Importantly, we have provided strong evidence that : (1) TBI produces derangements of specific cytoskeletal proteins resulting in different pathological profiles in axons and dendrites; (2) loss of these cytoskeletal proteins may not necessarily be related to cell death; (3) loss of cytoskeletal proteins may be at least partially attributable to receptor-coupled activation of calpains; and (4) systemic administration of putatively preferential inhibitors of calpain proteolysis can reduce cytoskeletal damage, including injury to axons and dendrites. The proposal incorporates 4 specific aims: (1) To determine whether moderate and severe magnitudes of TBI produce derangements of specific cytoskeletal proteins that reflect differences in the cellular localization of injury to neurons (e.g. dendrites versus axons); (2) To determine if the magnitude and duration of cytoskeletal proteins loss in various brain regions is related to the magnitude of neuronal injury, the ability of surviving neurons to synthesize new proteins and possible differences in the vulnerability of different proteins to proteolysis; (3) To determine if the loss of cytoskeletal proteins to TBI is at least partially attributable to the receptor coupled activation of Ca2+-dependent neutral proteases (e.g. calpains); (4) To determine if derangements of cytoskeletal proteins contribute to motor and spatial memory deficits produced by TBI.